Polynucleotide encoding a novel potassium channel with homology to the ether-a-go-go family, HEAG2

Abstract

The present invention provides novel polynucleotides encoding HEAG2 polypeptides, fragments and homologues thereof. Also provided are vectors, host cells, antibodies, and recombinant and synthetic methods for producing said polypeptides. The invention further relates to diagnostic and therapeutic methods for applying these novel HEAG2 polypeptides to the diagnosis, treatment, and/or prevention of various diseases and/or disorders related to these polypeptides. The invention further relates to screening methods for identifying agonists and antagonists of the polynucleotides and polypeptides of the present invention.

What is claimed is:  
     
         1 . A computer for producing a three-dimensional representation of a molecule or molecular complex, wherein said molecule or molecular complex comprises the structural coordinates of the PAS domain of HEAG2 as provided in Table IV, 
 wherein said computer comprises: 
 (a) A machine-readable data storage medium, comprising a data storage material encoded with machine readable data, wherein the data is defined by the set of structure coordinates of the model;  
 (b) a working memory for storing instructions for processing said machine-readable data;  
 (c) a central-processing unit coupled to said working memory and to said machine-readable data storage medium for processing said machine readable data into said three-dimensional representation; and  
 (d) a display coupled to said central-processing unit for displaying said three-dimensional representation.  
   
     
     
         2 . A method for identifying a HEAG2 mutant with altered biological properties, function, or activity 
 wherein said method comprises the steps of: 
 (a) using a model of the HEAG2 PAS domain according to the structural coordinates of said model as provided in Table IV to identify amino acids to mutate; and  
 (b) mutating said amino acids to create a mutant protein with altered biological function or properties.  
   
     
     
         3 . A method for designing or selecting compounds as potential modulators of HEAG2 
 wherein said method comprises the steps of: 
 (a) identifying a structural or chemical feature of HEAG2 using the structural coordinates of the HEAG2 PAS domain as provided in Table IV; and  
 (b) rationally designing compounds that bind to said feature.  
   
     
     
         4 . The method according to  claim 3  wherein the potential HEAG2 modulator is designed from a known modulator of potassium channel activity.  
     
     
         5 . The method according to  claim 2  wherein the HEAG2 mutant is a mutant with one or more mutations in the HEAG2 PAS domain comprised of amino acids E25 to about F134 of SEQ ID NO:2 according to Table IV with altered biological function or properties.  
     
     
         6 . The method according to  claim 3  wherein the HEAG2 feature is a hydrophobic patch region defined by all or any portion of residues L30, V41, M59, A112, I114, V122, L123, L125 of SEQ ID NO:2, in addition to the two conserved functional residues F28 and Y42 of SEQ ID NO:2, of the three-dimensional HEAG2 PAS domain structural model according to Table IV, or using a portion thereof.  
     
     
         7 . The computer according to  claim 1  wherein said structural coordinates of the HEAG2 three dimensional model is defined as having a root mean square deviation from the backbone atoms of said model of not more than about a member of the group consisting of: 4.0 Å; 3.5 Å; 3.0 Å; 2.5 Å; 2.0 Å; 1.5 Å; 1.0 Å; 0.9 Å; 0.8 Å; 0.7 Å; 0.6 Å; 0.5 Å; 0.4 Å; 0.3 Å; and 0.2 Å.  
     
     
         8 . The computer according to  claim 7  wherein said medium comprises a three dimensional model of a homolog of the HEAG2 PAS domain polypeptide.  
     
     
         9 . The computer according to  claim 7  wherein said medium comprises an analog of the three dimensional model of the HEAG2 PAS domain polypeptide, wherein said analog comprises one or more surrogate atoms that are substituted for original backbone carbon, nitrogen, or oxygen HEAG2 polypeptide atoms.  
     
     
         10 . The modulators identified by the method according to  claim 3 .  
     
     
         11 . The modulators identified by the method according to  claim 4 .  
     
     
         12 . The modulators identified by the method according to  claim 6 .  
     
     
         13 . A method of identifying a compound that modulates the biological activity of HEAG2, comprising the steps of, (a) combining a candidate modulator compound with a host cell comprising a vector capable of expressing HEAG2, wherein HEAG2 is expressed by the cell; and, (b) measuring an effect of the candidate modulator compound on the activity of the expressed HEAG2.  
     
     
         14 . The modulator identified by the method according to  claim 13 .  
     
     
         15 . The modulator of  claim 14  wherein said modulator is useful for treating a medical condition selected from the group consisting of: a disorder associated with aberrant amygdala function; fear; neurodevelopmental psychopathological disorders; schizophrenia; autism; aggression; and memory and emotional disorders.  
     
     
         16 . The modulator of  claim 14  wherein said modulator is useful for treating a medical condition selected from the group consisting of: a disorder associated with aberrant hypothalamus function; aggression; leptin receptor disorders; food intake disorders; energy expenditure disorders; physiological functions; neurophysin-related disorders; bone disorders; bone remodeling disease; appetite suppression; and motion sickness.  
     
     
         17 . A pharmaceutical composition comprising the modulator according to  claim 12 .  
     
     
         18 . A pharmaceutical composition comprising the modulator according to  claim 14.